Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

• the present invention relates to a novel azole derivative useful as a steroid 17-20 lyase inhibitor, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition.
• Steroid 17-20 lyase is formed from cholesterol and has a carbon substituent at the 17; 8 position, using 1H-OH pregnenolone and 17H-H progesterone as substrates. By cutting the bond between carbon and the carbon at position 20 of the carbon substituent, various androgens are produced. Therefore, by inhibiting the enzymatic activity of steroid 17-20 lyase, it is possible to suppress the production of androgen and the production of estrogen synthesized using androgen as a substrate, androgen and estrogen as hate factors. Prevention and treatment of the diseases involved are possible.
• a compound that inhibits steroid 17—20 lyase is considered to be a drug capable of blocking androgen strongly and capable of total androgen block even in view of its action, and is expected to be promising for the treatment of prostate cancer and the like. I have.
• steroid 17-20 lyase inhibitors can reduce estrogen, they are more effective therapeutic agents in benign prostatic hyperplasia than those that block only androgens, and It is expected to be a drug with fewer side effects.
• Non-steroidal steroid 17-20 lyase inhibitors include, for example, a substituted benzoimidazolyl group and an imidabryl group, which are fused bicyclic groups described in JP-A-64-89575, A (1H-imidazole-1-yl) methyl-substituted imidazole derivative linked at an elemental or methylene carbon is known.
• the compounds of the present invention are structurally different in that they have a fused tricyclic group, and are also excellent in pharmacological effects as described below.
• Lloyd 17-20 is a novel compound having lyase inhibitory activity and an inhibitory effect on testosterone synthesis.
• the compounds of the present invention differ from these compounds in that the azo ring is bonded to the fused benzene ring of the fused tricyclic group via one carbon atom.
• the present inventors have conducted intensive studies on compounds having a steroid 17-20 lyase inhibitory activity under the state of the art, and as a result, have found that an azole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof is The inventors of the present invention have found that they have an excellent steroid 17-20 lyase inhibitory action, and have completed the present invention.
• R 1 and R 2 are the same or different, and may be a hydrogen atom, a lower alkyl group, or a phenyl group which may be substituted with a halogen atom.
• X, Y same or different, a single bond, a methylene group, an oxygen atom, a group represented by the formula S (0) group or the formula one NR 4 represented by n
• R 3 , R 4 same or different, hydrogen atom or lower alkyl group
• n 0, 1 or 2)
• Preferred compounds in the compound of the present invention include those represented by the general formula (I):
• R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group;
• X is a single bond or a group represented by the formula S (0) n ;
• Y is a methylene group;
• group or Ah Ru ⁇ zone a group of the formula one NR 4 represented by Ichiru derivative or a salt thereof;
• an azole derivative or a salt thereof wherein X is a single bond and Y is a methylene group;
• an azole derivative which is 1- [11- (9H-fluoren-1-yl) ethyl] -11H-imidazole or a salt thereof.
• steroids that prevent and treat prostate cancer, benign prostatic hyperplasia, virilization, hirsutism, breast cancer, mastopathy, uterine fibroids and endometriosis.
• a case inhibitor is provided.
• the preferred pharmaceutical composition in this pharmaceutical composition is 1- [11- (9H-fluoren-1-yl) ethyl] 1-1H-imidazole or a pharmaceutically acceptable salt thereof as an active ingredient. 17-20 lyase inhibitor and the like.
• the compound of the present invention has a chemical structural characteristic in that a nitrogen atom of an azole ring is bonded to a carbon atom of a condensed tricyclic group containing X and Y via one carbon atom. It has a remarkably remarkable inhibitory activity as compared with the compound contained in the imidazolylmethylimidazole derivative described in JP-A-64-895975, which is a steroid 17-20 lyase inhibitor. It has pharmacological characteristics.
• lower means a carbon chain having 1 to 6 carbon atoms.
• a lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Therefore, specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and an isopentyl group.
• an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group is preferable, a methyl group and an ethyl group are more preferable, and a methyl group is further preferable.
• the “phenyl group optionally substituted by a halogen atom” may have a halogen atom at an arbitrary position of the phenyl group.
• Specific examples of the halogen atom include a fluorine atom and a chlorine atom. , A bromine atom, an iodine atom or any combination thereof.
• the number of halogen atoms is preferably 1 to 3.
• a phenyl group optionally substituted with a halogen atom is, for example, a fluorophenyl group, a chlorophenyl group, a bromophenyl group, a phenylphenyl group, a difluorophenyl group, a dichlorophenyl group, a dibromophenyl group, a bromophenyl group. Chlorophenyl, trichlorophenyl, bromodichlorophenyl, dichloromochlorophenyl, trichlorophenyl, bromodichlorophenyl, dichloromochlorophenyl, bromochlorofluorenyl, and the like. And a 3-phenylphenyl group is more preferred.
• a fluorenyl group a dibenzophenyl group, a dibenzofuryl group, a dibenzothiophenyl 9-oxide group, a phenothiazinyl group, a 10-methylphenothiazinyl group, and more preferably a 2-fluorenyl group.
• a fluorenyl group a dibenzophenyl group, a dibenzofuryl group, a dibenzothiophenyl 9-oxide group, a phenothiazinyl group, a 10-methylphenothiazinyl group, and more preferably a 2-fluorenyl group.
• the compounds of the present invention may form salts.
• the present invention includes pharmaceutically acceptable salts.
• Such salts include acid addition salts, and specific examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, and sulfuric acid.
• Acid addition salts with organic acids such as acids, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid.
• a salt with a pharmaceutically acceptable alkali metal or alkaline earth metal for example, sodium, potassium, magnesium, or calcium
• an organic amine with ammonia, triethylamine, or the like is used. Salts may also be formed.
• the compound of the present invention may have an asymmetric carbon atom depending on the type of the substituent, and such a compound has an optical isomer based on the asymmetric carbon atom and has two or more asymmetric carbon atoms. Sometimes, further diastereoisomers are present.
• the present invention includes isolated ones of these various isomers and a mixture of these isomers.
• the compounds of the present invention include all isolated compounds and mixtures thereof.
• the compounds of the present invention and salts thereof can be produced by applying various synthetic methods, utilizing characteristics based on the basic skeleton or types of substituents.
• Sulfonyloxy group Includes, for example, a methylsulfonyloxy group, a sulfonyloxy group, a p-toluenesulfonyloxy group, and the like.
• the alkyl derivative (a) which is a secondary or tertiary alcohol, is activated by halogenation or sulfonic acid esterification, and then, in the second step, a reaction with abour (II) is performed.
• the azole derivative (I) of the present invention can be obtained.
• the second step may be performed without isolating the product. No.
• thionyl chloride, phosphorus pentachloride, oxalyl chloride and the like can be reacted with an alcohol in an equimolar amount or in an excess amount, and halogenated. Alternatively, it may be reacted with p-toluenesulfonyl chloride, methylsulfonyl chloride, or the like to form a sulfonic ester.
• a halogenated hydrocarbon such as methylene chloride, chloroform, 1,2-dichloroethane, or an aromatic hydrocarbon such as benzene or toluene. The reaction is carried out at a temperature at which the solvent refluxes.
• an azole such as imidable or triazole (DO does not act as a base, so that no additional base is required.
• the azole (DI) is an alkyl derivative (E b )
• the reaction is carried out at 50 to 150 ° C. using 2 to 10 times the equivalent of the above.)
• azole itself can be used as a solvent, and dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, An organic solvent inert to this reaction, such as toluene or acetonitrile, may be further coexisted.
• a base is added, and an azole ( ⁇ ) such as imidazole or triabule is reacted with the alkyl derivative (H b) in an equal amount or a slightly excessive amount at 0 to 100 ° C. Is also good.
• the base for example, sodium hydride, potassium hydride, potassium bis (trimethylsilylamide), sodium amide, n-butyllithium, potassium t-butoxide, sodium, sodium methoxide, sodium ethoxide, etc. Can be.
• the reaction is performed in an organic solvent inert to this reaction, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, toluene, and acetonitrile.
• the compound (I) of the present invention is a dehydrating condensing agent such as 1,1′-carboxydiimidazole Can also be produced by performing a dehydration reaction between the compound (II) and the compound (H a) using
• dichloromethane chloroform, dichloroethane, tetrahydrofuran and the like can be used, and the reaction is carried out under ice cooling or heating under reflux.
• Examples of the protecting group include a dimethylsulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, an acetyl group, a Boc group and the like.
• the removal of the protecting group can be carried out by a commonly used known method.
• the compound of the present invention thus produced is isolated and purified as a free compound, a salt thereof, a hydrate, various solvates and the like.
• the pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting the compound to a conventional salt formation reaction.
• Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography.
• the optical isomer can be obtained by selecting an appropriate starting compound or by a racemic resolution method of a racemic compound (for example, a method of optically fractionating a diastereomer with a general optically active base). It can lead to more stereochemically pure isomers.
• the compound of the present invention has an effect of inhibiting the activity of steroid 17-20 lyase, which is an enzyme involved in producing androgen from cholesterol in vivo. Therefore, the compound of the present invention provides various diseases in which estrogen synthesized using androgen and androgen as a substrate is an aggressive factor, for example, prostate cancer, benign prostatic hyperplasia, androgenesis, hirsutism, breast cancer, breast disease, uterine fibroids, It is useful as a preventive and therapeutic agent for endometriosis and the like.
• Testes were removed from 10-week-old male Wistar rats, and the testes were homogenized, followed by centrifugation to obtain microsomes.
• a mixed solvent (2: 3) of methanol and tetrahydrofuran (2: 3) was added, followed by centrifugation, and the radioactivity of the substrate and the product (androstenedio ndrostenedione) and testosterone (testosterone) in the supernatant was determined.
• the inhibitory activity of the test compound on steroid 17-20 lyase was determined by high performance liquid chromatography (HPLC) with a radioisotope detector.
• test drug was orally administered to a 10-week-old male Wistar rat under fasting conditions.
• LH-RH (6 OngZrat) was administered intramuscularly to increase testosterone synthesis.
• decapitated blood was collected, and the testosterone concentration in the obtained serum was measured with a radioisotope Atsusei to determine the testosterone synthesis inhibitory activity.
• Examples disclosed as compounds of Example 87 The results of an experiment conducted on the control compound by the same method also showed that the compound of the present invention showed a 60-fold or more strong activity.
• the in vivo inhibitory activity of rat testosterone synthesis performed by the method described in the above-mentioned experimental method (2) was determined by comparing the testosterone to the control group when the test compound and the control compound were administered at a dose of 1 or 1 OmgZkg. It was expressed as the synthesis inhibition rate (%) (Table 2).
• control compound is disclosed in JP-A-64-85975.
• the compounds of the present invention also show a much better inhibitory effect on rat testosterone synthesis at a dose of 1Z10 of the control compound. did.
• compositions containing one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient are commonly used. It is prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, etc. It is administered parenterally.
• the dosage is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, body weight, etc. of the administration subject, but is usually 0.1 to 100 mg, preferably 0.1, per adult day.
• Parenteral administration in the range of 1 to 10 mg orally once or several times daily or in the range of 0.1 to 10 Omg per day in adults 0.1 to several times daily It is administered intravenously for 1 hour to 24 hours a day.
• a dose smaller than the above dose range may be sufficient.
• the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone.
• the metasilicate is mixed with magnesium aluminate.
• the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, A solubilizing or solubilizing agent such as formic acid or aspartic acid may be contained.
• Tablets or pills are gastric-soluble, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. Or it may be coated with a film of an enteric substance.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Including ethanol.
• This composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
• Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• aqueous diluents and suspension diluents include distilled water for injection and physiological saline.
• diluents for non-water-soluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
• Such compositions may further include additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing aids. .
• 1-[1-(9 H-fluorene-1-2-ethyl) ethyl] 1 1-H-midazole (8.88 g) was dissolved in ethyl acetate, and cooled with ice, 4 N hydrogen chloride monoethyl acetate 15 ml Was added. The precipitated crystals are collected by filtration, washed with ethyl acetate, and washed with 1- [11- (9H-fluoren-1-yl) ethyl]. 9.95 g of 1 H-imidazole hydrochloride was obtained.
• Tablets of 10 Omg per tablet were prepared using a mmx 7.8 R mortar. This tablet was coated with 350 g of a coating solution containing 20.3 g of hydroxypropylmethylcellulose, 2.8 g of polyethylene glycol, 2.8 g of polyethylene glycol, 11.2 g of titanium oxide and 0.7 g of talc in a coating apparatus (manufactured by Freund Corporation). It was sprayed to give a film-coated tablet coated with 5 mg per tablet.

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• 1994
  • 1994-09-28 AU AU77071/94A patent/AU679119B2/en not_active Ceased
  • 1994-09-28 HU HU9600813A patent/HUT75871A/hu unknown
  • 1994-09-28 US US08/619,629 patent/US5807880A/en not_active Expired - Fee Related
  • 1994-09-28 EP EP94927788A patent/EP0721943A4/en not_active Withdrawn
  • 1994-09-28 PL PL94313769A patent/PL313769A1/xx unknown
  • 1994-09-28 NZ NZ273681A patent/NZ273681A/en unknown
  • 1994-09-28 KR KR1019960701595A patent/KR960704852A/ko not_active Application Discontinuation
  • 1994-09-28 CN CN94193503A patent/CN1131944A/zh active Pending
  • 1994-09-28 WO PCT/JP1994/001593 patent/WO1995009157A1/ja not_active Application Discontinuation
  • 1994-09-28 CA CA002170874A patent/CA2170874A1/en not_active Abandoned
• 1996
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